Progestins are synthetic progestogens most frequently used for hormonal contraception (either alone or with an estrogen), as well as to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy. Estrogens, and especially the natural estrogen 17β estradiol (E2) on the other hand, are steroid compounds primarily functioning as female sex hormones and also used in certain oral contraceptives and in estrogen replacement therapy for post-menopausal women, as well as in hormone replacement therapy in various endocrinological conditions.
16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione is a progestin (also identified by the trade name NESTORONE® and referred to throughout this application as NES) comprising a 19-nor-progesterone derivative, with a structure close to the physiological hormone progesterone, which has been studied extensively in non-oral forms, including implants and vaginal rings for contraception. It has strong antiovulatory and progestational properties, and does not carry androgenic, estrogenic or glucocorticoid actions at therapeutic levels (1). Given its high anti-ovulatory potency when given systemically, only very low doses of NES are believed to be required for contraceptive efficacy and hence can be used in various non-oral delivery systems (2).
Estradiol (E2) is less potent than Ethinyl estradiol on the stimulation of estrogen-dependent liver proteins such as clotting factors, and has the potential to be a safer estrogen when combined with progestins for contraception. In addition it has been shown that estradiol when administered transdermally induces less risk of thrombotic events than oral estradiol when given to postmenopausal women (3).
It has been suggested that NES should be administered transdermally, either alone or in combination with estrogens such as estradiol. In particular, in a press release dated Nov. 28, 2007, Antares Pharma and The Population Council announced the results of a Phase 1 study for a contraceptive gel containing Nestorone® and estradiol. The purpose of the trial was to determine the absorption of Nestorone® and estradiol using the Antares transdermal gel system. The press release indicates that the data showed that an effective combined dose was identified for consistently delivering Nestorone®, and the serum levels matched target ranges expected to provide effective contraception. No serious adverse events were said to be recorded, and most subjects did not experience skin irritation.
As for the Antares gel system itself, this is disclosed, for example, in U.S. Pat. No. 7,470,433, the disclosure of which is incorporated herein by reference thereto.